This invention relates to a medical adhesive which is excellent in terms of release and percutaneous and per mucosa (hereinafter when referred to as percutaneous, the term includes per mucosa unless otherwise specified) absorption of medicinal ingredients from a preparation. Ease of producibility and stability of the preparation are also maintained.
A wide variety of preparations have been developed as adhesives for topical applications. In recent years, percutaneous administration has drawn attention as an efficient administration route for of medicines, and some adhesives for systemic actions, for example, preparations of nitroglycerin, isosorbide dinitrate, scopolamine, clonidine and estradiol are marketed. Most of the medicinal ingredients of these marketed preparations are suitable for percutaneous absorption in view of their physical properties and levels of effective concentration in blood, and are relatively easily formed into preparations.
However, medicinal ingredients consisting of hydrophilic compounds in the form of salts or the like are generally difficult to absorb percutaneously, and even release of the medicinal ingredients from the preparations is often difficult in matrix type adhesives in which the medicinal ingredients are incorporated or dispersed in polymers having relatively high hydrophobicity which are in wide use as the bases for adhesives.
As one of the means for improving absorbability of medicinal ingredients in such cases release from the preparations or percutaneous absorbability of the medicinal ingredients may be enhanced by increasing the fat-solubility of the medicinal ingredients themselves. For example, the medicinal ingredients may be used which have been in advance converted into their free bases in the base of the preparation; or free bases of the medicinal ingredients may be formed in the preparation.
As another means of improvement, incorporation of percutaneous absorption-promoting agents may be employed. Active studies have recently been made of absorption-promoting agents, and a number of absorption-promoting agents have been reported. Many examples of the adhesives containing absorption-promoting agents are described in, for example, unexamined Japanese Patent Application Nos. 24517/1986 and 221121/1986. However, the solubility of the medicinal ingredients in the base, release thereof from the base, or percutaneous absorbability of such adhesives are not satisfactory.
For the preparations in which the afore-mentioned medicinal ingredients having relatively high hydrophilicity are incorporated in bases mainly consisting of a hydrophobic polymer to exhibit solubility, release and percutaneous absorbability of the medicinal ingredients as expected, solubilizers for the medicinal ingredients are normally necessary. As a solubilizer for medicinal ingredients, water is generally selected in view of its low stimulus against the skin. As the examples of such adhesives in which water is used as a solubilizer, mention can be made of the adhesives as described in unexamined Japanese Patent Publication No. 02253/1985, wherein no absorption-promoting agent is contained, permitting relatively easy provision of stable plaster layers.
This invention relates to an improvement of the adhesives using water as a solubilizer as mentioned above.
The present invention provides a medical adhesive exhibiting excellent release and percutaneous absorption of the medicinal ingredient, which comprises a base mainly consisting of a hydrophobic polymer, an effective amount of a medicinal ingredient of low solubility in said hydrophobic polymer or poor in release from said hydrophobic polymer and an effective amount of percutaneous absorption-promoting agents which are admixed with or dispersed throughout said base. For the purpose of obtaining such an adhesive, a solubilizer for the medicinal ingredient is normally required.
The effective amounts of medicinal ingredients are generally determined primarily on the basis of the results of initial studies of physical properties, pharmacological effects, effective concentration in blood and the like of the medicinal ingredients, and the effective amounts are not in general determined taking account of the forms and usability of the preparations. This results in a problem that a stable preparation which exhibits the expected pharmacological effect cannot be necessarily obtained in many cases only by incorporating and mixing an effective amount of said medicinal ingredients, an effective amount of percutaneous absorption-promoting agents and the other ingredients.
In the present invention, for example, at least one percutaneous absorption-promoting agent is used. Percutaneous absorption-promoting agents are generally classified into two types, hydrophobic absorption-promoting agents and hydrophilic absorption-promoting agents as mentioned below, and they are normally used solely or in combination. In some cases, poor compatibility of the percutaneous absorption-promoting agents with solubilizers for medicinal ingredients or hydrophobic polymers, gives rise to separation of the ingredients during the course of production of the preparations or with the lapse of days after production, which results in failure to provide the desired adhesives.
Below, examples of the combination where compatibility is poor are given, including the above case.
a) a hydrophobic absorption-promoting agent and a hydrophilic absorption-promoting agent; PA0 b) a hydrophobic absorption-promoting agent and a solubilizer for medicinal ingredients; PA0 c) a hydrophobic polymer or a solution thereof in an organic solvent and a hydrophilic absorption-promoting agent; and PA0 d) a hydrophobic polymer or a solution thereof in an organic solvent and a solubilizer for medicinal ingredients. PA0 (1) A medical adhesive comprising a plaster layer containing the following ingredients, characterized in that the ingredient 2 is incorporated in a larger amount than the ingredient 5 and in an amount not less than 25% by weight relative to the total amount of the ingredients 1.about.5, and the plaster layer is a W/O type: PA0 (2) a medical adhesive as described in (1), which comprises a porous base layer in the plaster layer or in contact with the plaster layer.
As mentioned above, compatibility of each component is critical to feasibility of the preparations for those containing multiple components, and when components of the preparation have poor compatibility, the preparation lacks stability.